Identification of any publication, patent, or patent application in this section or any section of this application is not an admission that such publication is prior art to the present invention.
The preparation of 1,2-substituted 3,4-dioxo-1-cyclobutene compounds, for example, 2-Hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide (compound of formula I):
has been described in U.S. Pat. Nos. 7,123,445 (the '445 patent), issued Nov. 7, 2006, and 7,071,342 (the '342 patent), issued Jul. 4, 2006, the disclosure of each of which is incorporated herein in its entirety by reference. For examples of the preparation of the compound of Formula I, see the '455 patent at cols. 491 to 492, cols. 196 to 197, and cols. 251 to 256, and see the '342 patent, for example, at cols. 22 through 24.
Another example of the preparation of a 1,2-substituted 3,4-dioxo-1-cyclobutene compound, the preparation the 2-hydroxy-N,N-dimethyl-3-[[2-[[1(R)-[5-methyl-4-(1-methylethyl)-2-furanyl]propyl]amino)-3,4-dioxo-1-cyclobuten-1-yl]amino]-benzamide (the compound of Formula II),
is described in U.S. provisional patent application 60/819,541 (the '541 application) filed Jul. 7, 2006, the disclosure of which is incorporated by reference in its entirety. An example of the preparation of the compound of Formula II can be found in Example 2 of the '541 application. The aforementioned preparation schemes for the compounds of Formulae I and II are incorporated herein by reference in their entirety.
The synthesis method for preparing 1,2-substituted 3,4-dioxo-1-cyclobutene compounds described in the '342 patent generally follows Scheme I (which exemplifies the preparation of 2-Hydroxy-N,N-dimethyl-3-[[2-[[1(R)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-yl]amino]benzamide, the compound of Formula I).

The process for the preparation of the compound of Formula I shown in Scheme I is carried out by first preparing intermediate compound 2C from a dialkyl squarate, a strong skin sensitizer and irritant which is difficult to handle. Additionally, the conditions described in the aforementioned publications under which compounds 2C and 2Da are coupled in the second step of Scheme I produce an undesirable level of impurities admixed with the final product.
Moreover, the process for the preparation of the compound of Formula I shown in Scheme I requires in the first step a reaction between squarate compound 2A1 and intermediate compound IV(i), a 3-amino-2-hydroxy-benzamide compound which is unstable. The stability of the compound of Formula IV(i) makes it difficult to handle, store, and ship. Accordingly, this makes impracticable a process in which the compound of Formula IV(i) is made remotely from the process for making the compound of Formula 2C, or in which the process of making the compound of Formula 2C is not carried out contemporaneously with the preparation of the compound of Formula IV(i). Additionally, the product of Formula 2C provided using commercially available dialkylsquarate has a relatively large amount of impurities necessitating a product purification step prior to utilization in a synthesis of a compound of Formula Ia.
Additionally, as shown in step II of Scheme I, the compound of Formula I shown is prepared from coupling an aminofuran intermediate of Formula 2Da with intermediate compound 2C. The preparation of intermediate compound 2Da is described in U.S. Pat. No. 7,071,342 (the '342 patent) in cols. 35, line 1 to 39, line 20. The '342 patent describes a six step process for preparing the compound of Formula 2DA starting with the commercially available compound of Formula III. In the course of carrying out this process several changes of solvent are required, which leads to diminished isolated yields in the individual steps.
